Proceedings of the National Academy of Sciences
June 8, 2015
Manabu Fuchikami, Alexandra M. Thomas, Rongjian Liu et al.
282 citations
Ketamine's rapid and sustained antidepressant and anxiolytic effects depend on neuronal activity in the infralimbic prefrontal cortex (IL-PFC). Inactivating the IL-PFC in rodents completely blocked the behavioral effects of systemic ketamine, while direct microinfusion of ketamine into the IL-PFC reproduced those effects. Optogenetic stimulation of the IL-PFC alone also produced rapid, long-lasting antidepressant and anxiolytic effects, which were linked to increased number and function of spine synapses in layer V pyramidal neurons. The findings demonstrate that activating the IL-PFC is sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to those from systemic ketamine.
Current Neuropharmacology
March 10, 2016
Eric S. Wohleb, Danielle M. Gerhard, Alex Thomas et al.
148 citations
Major depressive disorder (MDD) is a common neuropsychiatric disease with limited treatment options that take weeks to work. Recent breakthroughs show that drugs like ketamine and scopolamine produce rapid and long-lasting antidepressant effects in MDD patients. Preclinical work in rodents indicates these effects arise from increased extracellular glutamate, elevated BDNF, activation of the mTORC1 cascade, and increased spine synapses in the prefrontal cortex (PFC). Both drugs work through converging molecular and cellular mechanisms in the PFC, antagonizing inhibitory interneurons to disinhibit pyramidal neurons, boosting glutamate. Specific NMDA and muscarinic acetylcholine receptor subtypes on GABAergic interneurons are promising targets for new rapid-acting antidepressants.
American Journal of Psychiatry
January 4, 2019
Satoshi Deyama, Eunyoung Bang, Eric S. Wohleb et al.
100 citations
The antidepressant effects of ketamine require vascular endothelial growth factor (VEGF) signaling through its receptor Flk-1 in excitatory neurons of the medial prefrontal cortex (mPFC). Deleting VEGF or Flk-1 from forebrain excitatory neurons, or blocking VEGF in the mPFC, prevented ketamine's behavioral effects in mice. Infusing VEGF directly into the mPFC produced rapid antidepressant-like actions similar to ketamine, but these were blocked by Flk-1 deletion. Local knockdown of Flk-1 in adult mPFC excitatory neurons also blocked ketamine's effects. Additionally, blocking neuronal VEGF signaling prevented the neurotrophic and synaptogenic actions of ketamine. Neuronal VEGF-Flk-1 signaling in the mPFC is essential for ketamine's rapid antidepressant actions.
Neurobiology of Disease
November 7, 2019
Sriparna Ghosal, Catharine H. Duman, Rong-Jian Liu et al.
94 citations
Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
Brain, behavior, and immunity
July 2, 2026
Samuel C Woodburn, Alexander M Kuhn, Kelly E Bosis et al.
Ketamine promotes spine growth on the apical dendrites of pyramidal neurons in the prefrontal cortex (PFC), and brain-derived neurotrophic factor (BDNF) signaling is critical for these effects. In mice, ketamine (10 mg/kg) reduced immobility in the forced swim test and increased dendritic spine density on PFC pyramidal neurons. These effects were associated with reduced microglia ramification and increased Bdnf expression in sorted PFC microglia. Mice with microglial Bdnf depletion (Cx3cr1Cre/+:Bdnffl/fl) showed decreased GluN2B levels in PFC synaptosomes, attenuated behavioral responses, and no change in dendritic spine density after ketamine. The results implicate microglia in the neurobiological and behavioral effects of ketamine.
bioRxiv Preprint Server
May 5, 2025
Samuel C Woodburn, Alexander M Kuhn, David T. Dadodsky et al.
preprint
Microglial BDNF is necessary for ketamine to increase synaptic density in the prefrontal cortex and produce antidepressant-like behavioral effects. Ketamine injection increased BDNF expression in microglia from the prefrontal cortex. Depleting BDNF specifically from microglia reduced levels of the NMDA receptor subunit GluN2B in prefrontal synapses and weakened antidepressant-like responses to ketamine, while also preventing the increase in dendritic spine density normally caused by ketamine. These results show that microglia, not just neurons, contribute to ketamine's effects on brain connections and mood, expanding the understanding of how immune cells in the brain participate in antidepressant responses.